The ALL-1 gene is involved in human acute leukemia chromosome translocations or partial tandem duplications. In addition, ALL-1 is the human homologue of Drosophila trithorax which is associated with early development of flies. The goal of the proposed studies is to understand the mode of action of the normal protein and determine how its leukemogenic derivatives trigger disease. Investigation of the normal protein would focus on identification and characterization of interacting cellular proteins as well as on response to ALL-1 leukemic fusion proteins. Attempts to identify and isolate cellular genes whose expression is up-regulated or down-regulated by the fusion proteins would involve screening of chips loaded with a very large number of cellular cDNAs, with probes derived from phenotypically similar tumors with and without ALL-1 rearrangements. In parallele, we will generate cell lines conditionally expressing the fusion proteins, and utilize differential display to identify genes regulated by the latters. Potential anti-apoptotic activity of ALL-1 fusion proteins will be examined by testing response of tumor lines producing the proteins to apoptotic stimuli, as well as by studying how these lines are affected by elimination of the fusion proteins or whether cultured cell lines conditionally expressing the proteins become protected from apoptotic death. Possible involvement of the partner proteins in cell death will also be investigated.